The present invention relates to novel benzimidazole derivatives, and, more precisely, to novel benzimidazole derivatives and their pharmaceutically acceptable salts having blood sugar level-depressing activity or PDE5-inhibiting activity. The present invention also relates to pharmaceutical compositions comprising, as an active ingredient, such benzimidazole derivatives or their salts.
The subject matter of the present invention is to provide novel benzimidazole derivatives and their pharmaceutically acceptable salts, and also pharmaceutical compositions which comprise, as an active ingredient, such benzimidazole derivatives or their pharmaceutically acceptable salts, and which are useful for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), or hypertension; or stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerous cachexia, or restenosis after PTCA.
The present inventors provide pharmaceutical compositions comprising, as an active ingredient, any of benzimidazole derivatives of the following formulae (I) to (IV) and (VIII) to (XIV), and their pharmaceutically acceptable salts, which is usable for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications such as diabetic nephropathy, diabetic neuropathy and diabetic retinopathy, syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), or hypertension; or stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerous cachexia, or restenosis after PTCA. 
In formula (I);
R1 represents a hydrogen atom, an arylsulfonyl group, or a lower alkyl group; said lower alkyl group may be substituted by an aryl group or an aryl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, an aryl-lower alkyl group, an aryl-lower alkyloxy group, a haloaryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, a cyanoaryl group, and a heterocyclic group, or by a heterocyclic group;
R2 represents a hydrogen atom, a lower cycloalkyl group, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, an amino group, a lower alkylamino group, a carboxyl group, an aryl group, or a lower alkyl group; said lower alkyl group may be substituted by a halogen atom, a lower alkoxy group, a cyano group, a chlorocarbonyl group, an aryl group, or a heterocyclic group;
R3 represents a carboxyl group, an esterified carboxyl group, an amidated carboxyl group, an amino group, an amido group, or a sulfonyl group; said amino group and said amido group may be substituted by an acyl group or a sulfonyl group; and a halogen atom, an amino group, or an acylamino group is bonded to said sulfonyl group; or R3 may be bonded to the skeleton via a lower alkylene or alkenylene group;
R4 represents a neutral substituent; and
n means an integer from 0 to 3. 
In formula (II);
R6 represents an aryl-lower alkyl group or an aryl-lower alkyl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, a cyanoaryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyl group, and a heterocyclic group;
R7 represents a lower alkyl group or a lower cycloalkyl group;
R8 represents a carbamoyl group, which may be substituted by a lower alkyl group, a lower alkyl group substituted by a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, an aryl group, a heterocyclic group, or a group of: 
in which R9 represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, an aryl-lower alkyl group, a hydroxy-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, a heterocyclic group, or an aryl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;
or R8 may be bonded to the skeleton via a lower alkylene or alkenylene group;
R4xe2x80x2 represents a hydrocarbon group or a halogenated hydrocarbon group; and
n means an integer from 0 to 3. 
In formula (III);
R6 represents an aryl-lower alkyl group or an aryl-lower alkyl group substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, a haloaryl group, a cyanoaryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyl group, and a heterocyclic group;
R7 represents a lower alkyl group or a lower cycloalkyl group;
R11 represents a substitutent of a formula: 
in which R12 represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, an aryl-lower alkyl group, a hydroxy-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, a heterocyclic group, or an aryl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;
or R11 may be bonded to the skeleton via a lower alkylene or alkenylene group;
R4xe2x80x2 represents a hydrocarbon group or a halogenated hydrocarbon group; and
n means an integer from 0 to 3. 
In formula (IV);
R13 represents an aryl-lower alkyl group or an aryl-lower alkyl group substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, a haloaryl group, a cyanoaryl group, an aryl-lower alkyl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, and a heterocyclic group;
R14 represents a lower alkyl group;
R15 represents a substitutent of a formula: 
in which R16 represents a lower alkyl group or an aryl group;
R4xe2x80x2 represents a hydrocarbon group or a halogenated hydrocarbon group; and
n means an integer from 0 to 3. 
In formula (VIII);
R1 represents a hydrogen atom, an arylsulfonyl group, or a lower alkyl group; said lower alkyl group may be substituted by an aryl group or an aryl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an aryl-lower alkyl group, a haloaryl-lower alkyloxy group, an arylsulfonylamino group, an arylcarbonylamino group, an arylcarbonyl group, an arylalkenyl group, a cyanoaryl group, and a heterocyclic group, or by a heterocyclic group;
R2 represents a hydrogen atom, a lower cycloalkyl group, a hydroxyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, an amino group, a lower alkylamino group, a carboxyl group, an aryl group, or a lower alkyl group; said lower alkyl group may be substituted by a halogen atom, a lower alkoxy group, a cyano group, a halocarbonyl group, an aryl group, or a heterocyclic group;
R25 represents an alkyl group having up to 8 carbon atoms, a lower cycloalkyl group, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-halogen alkyl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;
R26 represents a hydrogen atom or a lower alkyl group; provided that, when R25 and R26 are both lower alkyl groups, they may be bonded together to form a ring;
Y represents a carbonyl group or a lower alkylene group;
A represents a single bond, or a lower alkylene or alkenylene group;
R4xe2x80x2 represents a hydrocarbon group or a halogenated hydrocarbon group; and
n means an integer from 0 to 3. 
In formula (IX);
R27 represents a hydrogen atom, an alkyl group having up to 7 carbon atoms, a halo-lower alkyl group, an arylsulfonyl group, an aryl-lower alkyl group, a heterocyclic lower alkyl group, or a halo-heterocyclic lower alkyl group; and the aromatic ring moiety in said aryl-lower alkyl group may be substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, an aryloxy group, an arylcarbonyl group, an arylcarbonylamino group, and an aryl-lower alkyloxy group substituted by one or two halogen atoms;
R28 represents a hydrogen atom, an alkyl group having up to 7 carbon atoms, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower cycloalkyl group, an aryl group, an aryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, an amino group, or a carboxyl group;
R25 represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-lower alkyl group; and said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;
R26 represents a hydrogen atom or a lower alkyl group; provided that, when R25 and R26 are both lower alkyl groups, they may be bonded together to form a ring;
Y represents a carbonyl group or a lower alkylene group;
A represents a single bond, or a lower alkylene or alkenylene group; and
R29 represents a hydrogen atom or a lower alkyl group. 
In formula (X);
R30 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl-lower alkyl group of a formula: 
in which R31 represents a hydrogen atom, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, or an aryloxy group,
or represents an aryl-lower alkyloxy group or an aryl-lower alkyloxy group substituted by one or two halogen atoms, an arylsulfonyl group, a heterocyclic lower alkyl group, an arylcarbonylamino group, an arylcarbonyl group, an arylalkenyl group, or a lower alkylenedioxyaryl group; and the alkyl moiety in said aryl-lower alkyl group may be substituted by a lower alkyl group;
R32 represents a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a lower cycloalkyl group, an aryl group, an aryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-lower alkyl group, or a heterocyclic lower alkyl group;
R33 represents a carboxyl group, a lower alkoxycarbonyl group, a (2-cyanoaryl)oxycarbonyl group, or a group of a formula: 
in which Y represents a carbonyl group or a lower alkylene group; R34 represents a lower alkyl group or a lower alkyl group substituted by a substituted or unsubstituted aryl or heterocyclic group, or represents an aryl group or a heterocyclic group;
A represents a single bond, or a lower alkylene or alkenylene group;
R4xe2x80x2 represents a hydrocarbon group or a halogenated hydrocarbon group. R4xe2x80x2 may include an alkyl group, an aralkyl group, an alkynyl group, and halogenated groups of these. R4xe2x80x2 may be either saturated or unsaturated, may be either linear or cyclic, and may even be branched, as the case may be. For the halogenated groups, the type of the halogen therein is not specifically defined, and the number of the halogen substituents therein is not also specifically defined. n means an integer from 0 to 3. Therefore, one, two or three R4""s may be bonded to the skeleton, or no R4xe2x80x2 may be bonded thereto. The position of R4xe2x80x2 is not specifically defined and may be any of the ortho-position, the meta-position and the para-position relative to the other substituent. However, when R30 is a hydrogen atom, n is 0, or that is, no R4xe2x80x2 is bonded to the skeleton. 
In formula (XI);
R35 represents a hydrogen atom, an aryl group, a lower alkoxy-lower alkyl group, a lower alkyl group, or an aryl-lower alkyl group;
R36 represents a carboxyl group, a lower alkoxycarbonyl group, a heterocyclic lower alkylamino group, or a heterocyclic lower alkylcarbamoyl group;
R37 and R38 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, an aryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy group; and
A represents a single bond, or a lower alkylene or alkenylene group; provided that, when R35 is a lower alkyl group, A is a lower alkylene group or a lower alkenylene group. 
In formula (XII);
R37 and R38 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, an aryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy group;
R39 represents a lower alkyl group; and
R40 represents a hydrogen atom, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanesulfonyl group, or a carbamoyl group. 
In formula (XIII);
R37 and R38 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, an aryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy group; and
R7 represents a lower alkyl group or a lower cycloalkyl group. 
In formula (XIV);
R37 and R38 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, an aryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy group;
R7 represents a lower alkyl group or a lower cycloalkyl group;
R41 represents a 2-pyridylcarbamoyl group, a 2-carboxy-1-pyrrolidinocarbonyl group, an N-methyl-N-(2-pyridylmethyl)carbamoyl group, a homopiperidinocarbonyl group, a [2-(N-oxo)-pyridylmethyl]carbamoyl group, a 4-(dimethylamino)benzylcarbamoyl group, a piperonylcarbamoyl group, an N-methyl-N-(2-pyridyl)carbamoyl group, a thiomorpholinocarbonyl group, a halosulfonyl group, an aminosulfonyl group, an acylaminosulfonyl group, a lower alkoxycarbonyl group, or a carboxyl group;
R29 represents a hydrogen atom, or a lower alkyl group; provided that, when R41 is a lower alkylcarbonyl group or a carboxyl group, R29 is a lower alkyl group.
The present invention also provides novel benzimidazole derivatives of the above-mentioned (VIII) to (XIV) and their salts.
Benzimidazole derivatives to be provided by the present invention can be produced according to the following reaction formulae (a) to (f): 
In the above-mentioned reaction formulae, R1a to R1f may be selected from the above-mentioned R1, R6, R13, R17, R22, R23, R27, R30, or a substituted benzyl group of a formula: 
wherein R37 and R38 have the same meanings as those mentioned above. R2a to R2f may be selected from the above-mentioned R2, R7, R14, R18, R28, R32, R35 or R39. The substituents R3a to R3f may be selected from a substituent of a formula: 
with R25, R26, Y and A having the same meanings as those mentioned above, or from the above-mentioned R3, R8, R11, R15, R19, R24, AR33, AR36, NHR40, CN or R41. The substituents that define R3a through R3f can be mutually converted to each other. For example, as in the step (g) or (h) mentioned below, the ester (26) can be converted into the corresponding acid (27) or acid halide (28). The desired benzimidazoles can be produced through the reaction of these compounds with amines or sulfonamides. It is further possible to give various derivatives, as in the step (i) or (j) or (k) or (l) or (m) or (n) mentioned below. Such conversion of the groups, R3a through R3f can be effected at any stage in the steps (a) through (f), while depending on the stability of R1a to R1f as well as R2a to R2f in the compounds and even on the easiness in the isolation of the products formed. 
In this reaction formula, R9 represents a lower alkyl group; and R1a-f and R2a-f have the same meanings as those mentioned above. 
In this reaction formula, Zxe2x80x2 represents a chlorine atom or a bromine atom; and R1a-f and R2a-f have the same meanings as those mentioned above. 
In this reaction formula, R1a-f and R2a-f have the same meanings as those mentioned above. 
In this reaction formula, R1a-f and R2a-f have the same meanings as those mentioned above.
In the reaction step (a), a compound of formula (1) may be reacted with a base, such as sodium hydride, lithium diisopropylamide, lithium hydrogencarbonate, lithium carbonate, lithium hydroxide, sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, potassium carbonate, potassium hydroxide or the like, and with a compound to be represented by R1aZ (where Z represents a chlorine atom, a bromine atom, a toluenesulfonyloxy group, or a methanesulfonyloxy group) to give a compound of formula (2). The compound of formula (2) may be 1) reduced with reduced iron or zinc under an acidic condition, or 2) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in a hydrogen atmosphere, or 3) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in the presence of formic acid, or 4) reduced with sodium hydrosulfite, to be converted into a compound of formula (3). In the process 1), the compound of formula (3) is often cyclized in the reaction system directly into a compound of formula (4). Depending on the compound of formula (2) being reduced, the compound of formula (4) may be partly formed in any of the processes 1) to 4). The compound of formula (3) may be processed with a carboxylic acid, a sulfonic acid or an inorganic acid, such as acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or the like, to give the compound of formula (4).
In the step (b), a compound of formula (5) is may be hydrolyzed or solvolyzed with a base, such as lithium hydrogencarbonate, lithium carbonate, lithium hydroxide, sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, potassium carbonate, potassium hydroxide or the like, or with a carboxylic acid, a sulfonic acid or inorganic acid, such as acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or the like, into a compound of formula (6). The compound of formula (6) may be reacted with a base, such as sodium hydride, lithium diisopropylamide, lithium hydrogencarbonate, lithium carbonate, lithium hydroxide, sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, potassium carbonate, potassium hydroxide or the like, and with a compound to be represented by R1bZ (where Z represents a chlorine atom, a bromine atom, a toluenesulfonyloxy group, or a methanesulfonyloxy group) to give a compound of formula (7). The compound of formula (7) may be 1) reduced with reduced iron or zinc under an acidic condition, or 2) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in a hydrogen atmosphere, or 3) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in the presence of formic acid, or 4) reduced with sodium hydrosulfite, to be converted into a compound of formula (8). A compound of formula (9) can be produced from the compound of formula (8) and the corresponding carboxylic acid or acid chloride or acid bromide or acid anhydride.
In the step (c), a compound of formula (11) can be produced from a compound of formula (10) and a compound to be represented by R1cNH2. The conversion of the compound of formula (11) to a compound of formula (13) is the same as that of the compound of formula (7) to the compound of formula (9) in the step (b).
In the step (d), a compound of formula (14) may be 1) reduced with a transition metal catalyst such as typically palladium, platinum, ruthenium or nickel in a hydrogen atmosphere, or 2) reduced with sodium hydrosulfite to give a compound of formula (15). The compound of formula (15) may be reacted with a base, such as lithium hydrogencarbonate, lithium carbonate, lithium hydroxide, sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, potassium carbonate, potassium hydroxide or the like, and with a compound to be represented by R1dZ (where Z represents a chlorine atom, a bromine atom, a toluenesulfonyloxy group, or a methanesulfonyloxy group) to give a compound of formula (16). The compound of formula (16) may be treated with a carboxylic acid, a sulfonic acid or an inorganic acid, such as acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or the like, to give a compound of formula (17).
In the step (e), a compound of formula (18) may be (1) reduced with reduced iron or zinc under an acidic condition, or 2) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in a hydrogen atmosphere, or 3) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in the presence of formic acid, or 4) reduced with sodium hydrosulfite, to be converted into a compound of formula (19). A compound of formula (20) can be produced from the compound of formula (19) and the corresponding carboxylic acid or acid anhydride or acid chloride or acid bromide. The compound of formula (20) may be reacted with a base, such as sodium hydride, lithium diisopropylamide, lithium hydrogencarbonate, lithium carbonate, lithium hydroxide, sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, potassium carbonate, potassium hydroxide or the like, and with a compound to be represented by R1eZ (where Z represents a chlorine atom, a bromine atom, a toluenesulfonyloxy group, or a methanesulfonyloxy group) to give a compound of formula (21).
In the process comprising the above-mentioned step, in general, the product may be obtained as a mixture comprising the compound of formula (21) where R3e is positioned in the 5-position and that where it is in the 6-position, or a mixture comprising the compound of formula (21) where R3e is positioned in the 4-position and that where it is in the 7-position. Each compound of formula (21) can be purified from the mixture as the single compound, for example, through recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography or the like.
In the step (f), a compound of formula (22) may be 1) reduced with reduced iron or zinc under an acidic condition, or 2) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in a hydrogen atmosphere, or 3) reduced with a transition metal catalyst, such as typically palladium, platinum, ruthenium or nickel, in the presence of formic acid, or 4) reduced with sodium hydrosulfite, to be converted into a compound of formula (23). In the process 1), the compound of formula (23) is often cyclized in the reaction system directly into a compound of formula (24). Depending on the compound of formula (22) being reduced, the compound of formula (24) may be partly formed in any of the processes 1) to 4). The compound of formula (23) may be processed with a carboxylic acid, a sulfonic acid or an inorganic acid, such as acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or the like, to give the compound of formula (24). The compound of formula (24) may be converted into a benzimidazole compound of formula (25) in the same manner as in the step (e) of converting the compound of formula (20) into the compound of formula (21). In this step, in general, the product may be obtained as a mixture comprising the compound of formula (25) where R3f is positioned in the 5-position and that where it is in the 6-position, or a mixture comprising the compound of formula (25) where R3f is positioned in the 4-position and that where it is in the 7-position. Each compound of formula (25) can be purified from the mixture as the single compound, for example, through recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography or the like.
In the step (g), a compound of formula (26) may be hydrolyzed with a base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or the like, to give a compound of formula (27). The compound of formula (27) may be reacted with a carbonyldiimidazole and then with amines or sulfonamides in the presence of a base to give different benzimidazole derivatives.
In the step (h), the compound of formula (27) may be processed with thionyl chloride or thionyl bromide or phosphorus trichloride or phosphorus pentachloride or phosphorus oxychloride to be converted into its acid halide of formula (28). The compound of formula (28) may be reacted with amines or sulfonamides to give different benzimidazole derivatives.
In the step (i), a compound of formula (29) may be reacted with titanium tetrachloride to give a compound of formula (30).
In the step (j), the compound of formula (27) may be reacted with an azide, such as typically diphenylphosphorylazide, in the presence of an alcohol, such as typically t-butanol, to give a compound of formula (31). The compound of formula (31) may be decomposed with an acid to give a compound of formula (32). The compound of formula (32) may be reacted with a compound to be represented by R40Z (where Z represents a chlorine atom or a bromine atom) to give a compound of formula (33). 
wherein Rg, R1a-f, and R2a-f have the same meanings as those mentioned above; and Z represents a chlorine atom, a bromine atom, a toluenesulfonyloxy group, or a methanesulfonyloxy group. 
wherein R1a-f, R2a-f and Z have the same meanings as those mentioned above. 
wherein R1a-f, R2a-f and R9 have the same meanings as those mentioned above. 
wherein R1a-f, R2a-f and R9 have the same meanings as those mentioned above.
In the step (k), the compound of formula (26) may be reduced into a compound of formula (34), which may be then treated with thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, methanesulfonyl chloride, toluenesulfonyl chloride or the like to be converted into a compound of formula (35).
In the step (1), the compound of formula (35) may be reacted with sodium cyanide or potassium cyanide to give a compound of formula (36), which may be then hydrolyzed with lithium hydroxide or sodium hydroxide or potassium hydroxide to give a carboxylic acid of formula (37).
In the step (m), a compound of formula (38) to be obtained by oxidizing the compound of formula (34) may be reacted with an alkyl (triphenylphosphoranilidene)acetate to give a compound of formula (39), which may then be hydrolyzed with lithium hydroxide or sodium hydroxide or potassium hydroxide to give a carboxylic acid of formula (40). The compound of formula (35), (37) or (40) may be reacted with amines or sulfonylamides to give different benzimidazole compounds.
In the step (n), the compound of formula (39) may be reduced with palladium, platinum, ruthenium or the like transition metal catalyst in a hydrogen atmosphere or in the presence of formic acid to give a compound of formula (41).
The following compounds of: 
where R1a-f, R2a-f and R3a-f have the same meanings as those mentioned above; and R4a-f may be selected from the above-mentioned R4, R4xe2x80x2 and R29,
can be produced according to the steps (a) to (f) while starting from the following compounds of: 
where R1a, R2a and R3a have the same meanings as those mentioned above; and R4a may be selected from the above-mentioned R4, R4xe2x80x2 and R29; 
where R1b, R2b and R3b have the same meanings as those mentioned above; and R4b may be selected from the above-mentioned R4, R4xe2x80x2 and R29; 
where R1c, R2c and R3c have the same meanings as those mentioned above; and R4c may be selected from the above-mentioned R4, R4xe2x80x2 and R29; 
where R1d, R2d and R3d have the same meanings as those mentioned above; and R4d may be selected from the above-mentioned R4, R4xe2x80x2 and R29; 
where R1e, R2e and R3e have the same meanings as those mentioned above; and R4e may be selected from the above-mentioned R4, R4xe2x80x2 and R29; 
where R1f, R2f and R3f have the same meanings as those mentioned above; and R4f may be selected from the above-mentioned R4, R4xe2x80x2 and R29.
If desired, the intermediates formed in the above-mentioned steps may optionally be purified, prior to being subjected to the next step, through any conventional purification including, for example, recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography and the like. If also desired, the final products of the compounds of the present invention may optionally be purified through any conventional purification which is employed in the art of purifying organic compounds and which includes, for example, recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography and the like. To identify these compounds, employable is any of NMR spectrography, mass spectrography, IR spectrography, elementary analysis, measurement of melting point and others.
Preferred embodiments and their details of various definitions as referred to herein to be within the scope of the present invention are described below.
Unless otherwise specifically indicated herein, the terminology xe2x80x9clowerxe2x80x9d indicates that the group has from 1 to 6 carbon atoms. As preferred examples of the lower alkyl group as referred to herein, mentioned are linear or branched alkyl groups including a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a sec-pentyl group, a t-pentyl group, a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methyl propyl groups, etc.
The alkyl group having up to 7 carbon atoms is a linear or branched alkyl group, including a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a sec-pentyl group, a t-pentyl group, a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group, an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 1-ethylpentyl group, a 2-ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a 1,1-dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutyl group, etc.
The alkyl group having up to 8 carbon atoms is a linear or branched alkyl group, including a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a sec-pentyl group, a t-pentyl group, a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group, an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 1-ethylpentyl group, a 2-ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a 1,1-dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutyl group, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group, a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a 1,1-dimethylhexyl group, a 2,2-dimethylhexyl group, a 3,3-dimethylhexyl group, a 4,4-dimethylhexyl group, a 5,5-dimethylhexyl group, a 1-propylpentyl group, a 2-propylpentyl group, etc.
The lower alkylene group is an alkylene group having 6 or less carbon atoms, including a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, a hexylene group, etc. The lower alkenylene group is an alkenylene group having 6 or less carbon atoms, including an ethenylene group, a 1-propenylene group, a 2-propenylene group, a 1-butenylene group, a 2-butenylene group, a 3-butenylene group, a 1-pentenylene group, a 2-pentenylene group, a 3-pentenylene group, a 4-pentenylene group, a 1-hexenylene group, a 2-hexenylene group, a 3-hexenylene group, a 4-hexenylene group, a 5-hexenylene group, etc.
The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferred are a fluorine atom, a chlorine atom and a bromine atom.
The halo-lower alkyl group is a linear or branched alkyl group having up to 8 carbon atoms, which is substituted with one or more halogen atoms selected from fluorine, chlorine, bromine and iodine atoms. Preferred is a linear or branched alkyl group having up to 8 carbon atoms, which is substituted with one or more halogen atoms selected from fluorine, chlorine and bromine atoms. It includes, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 1-fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 1,2-difluoroethyl group, a 1,2-dichloroethyl group, a 1,2-dibromoethyl group, a 2,2,2-trifluoroethyl group, a heptafluoroethyl group, a 1-fluoropropyl group, a 1-chloropropyl group, a 1-bromopropyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 3-bromopropyl group, a 1,2-difluoropropyl group, a 1,2-dichloropropyl group, a 1,2-dibromopropyl group, a 2,3-difluoropropyl group, a 2,3-dichloropropyl group, a 2,3-dibromopropyl group, a 3,3,3-trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a 4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a 4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, a perfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a 2-bromopentyl group, a 5-fluoropentyl group, a 5-chloropentyl group, a 5-bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a 2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a 6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a 2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptyl group, a 7-fluoroheptyl group, a 7-chloroheptyl group, a 7-bromoheptyl group, a perfluoroheptyl group, etc.
The lower alkoxy group is a linear or branched alkyloxy group having up to 6 carbon atoms. It includes, for example, a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an i-butyloxy group, a sec-butyloxy group, a t-butyloxy group, an n-pentyloxy group, an i-pentyloxy group, a sec-pentyloxy group, a t-pentyloxy group, a 2-methylbutoxy group, an n-hexyloxy group, an i-hexyloxy group, a t-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a 1-ethylbutyloxy group, a 2-ethylbutyloxy group, a 1,1-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a 1-ethyl-1-methylpropyloxy group, etc. Preferred are a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an i-butyloxy group, a sec-butyloxy group, a t-butyloxy group, etc.
The lower cycloalkyl group is a cycloalkyl group having from 3 to 7 carbon atoms, and preferably includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc. More preferred are a cyclopropyl group, a cyclobutyl group, etc.
The lower alkoxy-lower alkyl group is a linear or branched alkyl group having up to 8 carbon atoms, as substituted with a linear or branched alkyloxy group having up to 8 carbon atoms. For example, this includes a methoxymethyl group, a methoxyethyl group, a methoxypropyl group, a methoxybutyl group, a methoxypentyl group, a methoxyhexyl group, a methoxyheptyl group, a methoxyoctyl group, an ethoxymethyl group, an ethoxyethyl group, an ethoxybutyl group, an ehtoxypentyl group, an ehtoxyhexyl group, an ethoxyheptyl group, a ethoxyoctyl group, a propyloxymethyl group, a propyloxyethyl group, a propyloxypropyl group, a propyloxybutyl group, a propyloxypentyl group, an i-propyloxymethyl group, an i-propyloxyethyl group, an i-propyloxypropyl group, an i-propyloxybutyl group, an i-propyloxypentyl group, a butyloxymethyl group, a butyloxyethyl group, a butyloxypropyl group, a butyloxybutyl group, an i-butyloxymethyl group, an i-butyloxyethyl group, an i-butyloxypropyl group, an i-butyloxybutyl group, a sec-butyloxymethyl group, a sec-butyloxyethyl group, a sec-butyloxypropyl group, a sec-butyloxybutyl group, a t-butyloxymethyl group, a t-butyloxyethyl group, a t-butyloxypropyl group, a t-butyloxybutyl group, a pentyloxymethyl group, a pentyloxyethyl group, a pentyloxypropyl group, a pentyloxybutyl group, a hexyloxymethyl group, a hexyloxyethyl group, a hexyloxypropyl group, etc.
The tri-lower alkylsilyl-lower alkyl group is a lower alkyl group, such as that mentioned hereinabove, to which is bonded a trimethylsilyl group, a triethylsilyl group, a tripropylsilyl group or the like.
The lower alkylamino group is a linear or branched alkylamino group having up to 6 carbon atoms. This includes, for example, a methylamino group, an ethylamino group, an n-propylamino group, an i-propylamino group, an n-butylamino group, an i-butylamino group, a sec-butylamino group, a t-butylamino group, an n-pentylamino group, an i-pentylamino group, a sec-pentylamino group, a t-pentylamino group, a 2-methylbutylamino group, an n-hexylamino group, a 1-methylpentylamino group, a 2-methylpentylamino group, a 3-methylpentylamino group, a 4-methylpentylamino group, a 1-ethylbutylamino group, a 2-ethylbutylamino group, a 3-ethylbutylamino group, a 1,1-dimethylbutylamino group, a 2,2-dimethylbutylamino group, a 3,3-dimethylbutylamino group, a 1-ethyl-1-methylpropylamino group, etc. More preferred are a methylamino group, an ethylamino group, an n-propylamino group, an i-propylamino group, an n-butylamino group, an i-butylamino group, a sec-butylamino group, a t-butylamino group, etc.
The lower alkylthio group is a linear or branched alkylthio group having up to 6 carbon atoms. This includes, for example, a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, a sec-butylthio group, a t-butylthio group, an n-pentylthio group, an i-pentylthio group, a sec-pentylthio group, a t-pentylthio group, a 2-methylbutylthio group, an n-hexylthio group, an i-hexylthio group, a t-hexylthio group, a sec-hexylthio group, a 2-methylpentylthio group, a 3-methylpentylthio group, a 1-ethylbutylthio group, a 2-ethylbutylthio group, a 1,1-dimethylbutylthio group, a 2,2-dimethylbutylthio group, a 3,3-dimethylbutylthio group, a 1-ethyl-1-methylpropylthio group, etc. More preferred are a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, a sec-butylthio group, a t-butylthio group, etc.
The lower alkylthio-lower alkyl group is a linear or branched alkyl group having up to 6 carbon atoms, such as that mentioned hereinabove, as substituted with a linear or branched alkylthio group having up to 6 carbon atoms, such as that mentioned hereinabove.
The lower alkoxycarbonyl group is a linear or branched alkyloxycarbonyl group with a alkyl moiety having up to 6 carbon atoms. This includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group, an i-propyloxycarbonyl group, an n-butyloxycarbonyl group, an i-butyloxycarbonyl group, a sec-butyloxycarbonyl group, a t-butyloxycarbonyl group, an n-pentyloxycarbonyl group, an i-pentyloxycarbonyl group, a sec-pentyloxycarbonyl group, a t-pentyloxycarbonyl group, a 2-methylbutyloxycarbonyl group, an n-hexyloxycarbonyl group, an i-hexyloxycarbonyl group, a t-hexyloxycarbonyl group, a sec-hexyloxycarbonyl group, a 2-methylpentyloxycarbonyl group, a 3-methylpentyloxycarbonyl group, a 1-ethylbutyloxycarbonyl group, a 2-ethylbutyloxycarbonyl group, a 1,1-dimethylbutyloxycarbonyl group, a 2,2-dimethylbutyloxycarbonyl group, a 3,3-dimethylbutyloxycarbonyl group, a 1-ethyl-1-methylpropyloxycarbonyl group, etc. More preferred are a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group, an i-propyloxycarbonyl group, an n-butyloxycarbonyl group, an i-butyloxycarbonyl group, a sec-butyloxycarbonyl group, a t-butyloxycarbonyl group.
The lower alkanoyl group is a linear or branched alkylcarbonyl group having up to 6 carbon atoms. This includes, for example, a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an i-propylcarbonyl group, an n-butylcarbonyl group, an i-butylcarbonyl group, a sec-butylcarbonyl group, a t-butylcarbonyl group, an n-pentylcarbonyl group, an i-pentylcarbonyl group, a sec-pentylcarbonyl group, a t-pentylcarbonyl group, a 2-methylbutylcarbonyl group, an n-hexylcarbonyl group, an i-hexylcarbonyl group, a t-hexylcarbonyl group, a sec-hexylcarbonyl group, a 2-methylpentylcarbonyl group, a 3-methylpentylcarbonyl group, a 1-ethylbutylcarbonyl group, a 2-ethylbutylcarbonyl group, an 1,1-dimethylbutylcarbonyl group, a 2,2-dimethylbutylcarbonyl group, a 3,3-dimethylbutylcarbonyl group, a 1-ethyl-1-methylpropylcarbonyl group, etc. More preferred are a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an i-propylcarbonyl group, an n-butylcarbonyl group, an i-butylcarbonyl group, a sec-butylcarbonyl group, a t-butylcarbonyl group, etc.
The lower alkanesulfonyl group is a linear or branched alkanesulfonyl group having up to 6 carbon atoms. This includes, for example, a methanesulfonyl group, an ethanesulfonyl group, a 1-propanesulfonyl group, a 2-propanesulfonyl group, a 1-butanesulfonyl group, a 2-butanesulfonyl group, a 1,1-dimethylethanesulfonyl group, a 1-(2-methylpropane)sulfonyl group, a 1-pentanesulfonyl group, a 2-pentanesulfonyl group, a 3-pentanesulfonyl group, a 1-(3-methylbutane)sulfonyl group, a 1,1-dimethylpropanesulfonyl group, a 1-hexanesulfonyl group, a 2-hexanesulfonyl group, a 3-hexanesulfonyl group, a 1-(2-methylpentane)sulfonyl group, a 1-(3-methylpentane)sulfonyl group, a 1-(4-methylpentane)sulfonyl group, a 2-ethylbuthanesulfonyl group, a 3-ethylbutanesulfonyl group, a 1,1-dimethylbutanesulfonyl group, a 2,2-dimethylbutanesulfonyl group, a 3,3-dimethylbutanensulfonyl group, a 1-ethyl-1-methylpropanesulfonyl group, etc.
The aryl group includes, for example, a phenyl group, a naphthyl group, etc. The terminology xe2x80x9cnaphthylxe2x80x9d as referred to herein includes 1-naphthyl and 2-naphthyl. The benzene ring or the naphthalene ring in this group may optionally be substituted by one or more substituents selected from a halogen atom, a lower alkyl group, a cyano group, a nitro group, a trifluoromethyl groups and the like, such as those mentioned hereinabove.
The arylsulfonyl group is a sulfonyl group, to which is bonded an aryl group such as that mentioned hereinabove, and includes, for example, a benzenesulfonyl group, a toluenesulfonyl group, a naphthalenesulfonyl group, etc.
The aryl-lower alkyl group is a lower alkyl group, such as that mentioned hereinabove, to which is bonded an aryl group such as that mentioned hereinabove, and includes, for example, a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a phenylpropyl group, a phenylbutyl group, a phenylpentyl group, a phenylhexyl group, a naphthylmethyl group, a naphthylethyl group, a naphthylpropyl group, a naphthylbutyl group, a naphthylpentyl group, a naphthylhexyl group, etc.
The aryl-lower alkyloxy group includes, for example, a benzyloxy group, a 1-phenylethyloxy group, a 2-phenylethyloxy group, a phenylpropyloxy group, a phenylbutyloxy group, a phenylpentyloxy group, a phenylhexyloxy group, a naphthylmethyloxy group, a naphthylethyloxy group, a naphthylpropyloxy group, a naphthylbutyloxy group, a naphthylpentyloxy group, etc., in which the benzene ring or the naphthalene ring may optionally be substituted.
The arylsulfonyl-lower alkyl group is a lower alkyl group, such as that mentioned hereinabove, to which is bonded an arylsulfonyl group such as that mentioned hereinabove, and includes, for example, a benzenesulfonylmethyl group, a toluenesulfonylmethyl group, a naphthalenesulfonylmethyl group, etc.
The arylsulfonylamino group is an amino group to which is bonded an arylsulfonyl group such as that mentioned hereinabove, and this includes, for example, a benzenesulfonylamino group, a toluenesulfonylamino group, a naphthalenesulfonylamino group, etc.
The aryloxy group is an aryl group, such as that mentioned hereinabove, to which is bonded an oxygen atom, and this includes, for example, a phenoxy group, a 1-naphthoxy group, a 2-naphthoxy group, etc.
The arylcarbonyl group is a carbonyl group to which is bonded an aryl group such as that mentioned hereinabove, and this includes, for example, a phenylcarbonyl group, a naphthylcarbonyl group, etc.
The arylcarbonylamino group is an amino group to which is bonded an arylcarbonyl group such as that mentioned hereinabove, and this includes, for example, a phenylcarbonylamino group, a naphthylcarbonylamino group, etc.
The aryl-lower alkenyl group is an alkenyl group having 6 or less carbon atoms, which is substituted by an aryl group such as that mentioned hereinabove, and this includes, for example, a phenylethenyl group, a naphthylethenyl group, etc.
The heterocyclic group includes, for example, a pyridyl group, a quinolyl group, an isoquinolyl group, a thiazolyl group, a thiadiazolyl group, a benzofuranyl group, a dibenzofuranyl group, a thianaphthalenyl group, a 1H-1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrimidinyl group, an indolyl group, a benzimidazolyl group, etc. The heterocyclic group may optionally be substituted by one or more substituents of halogen atoms and lower alkyl groups, such as those mentioned hereinabove, and the substituted heterocyclic group of that type includes, for example, a haloisoquinolyl group, a methylisoquinolyl group, etc.
The heterocyclic lower alkyl group means a lower alkyl group, such as that mentioned hereinabove, as substituted by a heterocyclic group, such as that mentioned hereinabove. This includes, for example, a pyridylmethyl group. The halo-heterocyclic lower alkyl group is a heterocyclic lower alkyl group, such as that mentioned hereinabove, in which the heterocyclic moiety is substituted with one or more halogens.
The heterocyclic lower alkylamino group is an amino group as substituted with a heterocyclic lower alkyl group, such as that mentioned hereinabove, and this includes, for example, a pyridylmethylamino group, etc. The heterocyclic lower alkylcarbamoyl group is a carbamoyl group as substituted with a heterocyclic lower alkyl group, such as that mentioned hereinabove, and this includes, for example, a pyridylmethylcarbamoyl group, etc.
The terminology xe2x80x9cpyridylxe2x80x9d as referred to herein includes 2-pyridyl, 3-pyridyl and 4-pyridyl, for which the bonding position is not specifically defined. The same shall apply to the other heterocyclic groups as referred to herein, or that is, the bonding positions of the heterocyclic groups as referred to herein are not specifically defined.
The lower alkylenedioxybenzyl group includes, for example, a methylenedioxybenzyl group, an ethylenedioxybenzyl group, a propylenedioxybenzyl group, etc.
A suitable heterocyclic group used herein means a saturated or unsaturated mono- or polycyclic hetero ring containing at least one hetero atom such as an oxygen atom, a sulfur atom, a nitrogen atom, etc.
Preferable examples thereof include the following heterocyclic groups:
7- to 12-membered, preferably 9- or 10-membered unsaturated condensed heterocyclic group (preferably bicyclic group) having 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolidinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, or the like;
7- to 12-membered, preferably 9- or 10-membered unsaturated condensed heterocyclic group (preferably bicyclic group) having 1 to 3 sulfur atoms or S,S-dioxide thereof, such as dithianaphthalenyl (e.g. 4H-1,3-dithianaphthalenyl, 1,4-dithianaphthalenyl, etc.), benzothiophenyl or S,S-dioxide thereof (e.g. benzo[a]thiophenyl or S,S-dioxide thereof, benzo[b]thiophenyl or S,S-dioxide thereof, etc.), or the like;
3- to 8-membered, preferably 5- or 6-membered unsaturated hetero monocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,3-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), dihydrotriazinyl (e.g. 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), or the like;
3- to 8-membered, preferably 5- or 6-membered saturated hetero monocyclic group having 1 to 4 nitrogen atoms, such as azetydinyl, pyrrolidinyl, imidazolydinyl, piperidinyl, pyrazolydinyl, piperadinyl, or the like;
7- to 12-membered, preferably 9- or 10-membered unsaturated condensed heterocyclic group (preferably bicyclic group) having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzooxazolyl, benzooxadiazolyl, or the like;
3- to 8-membered, preferably 5- or 6-membered unsaturated hetero monocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isooxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), or the like;
3- to 8-membered, preferably 5- or 6-membered saturated hetero monocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl or the like;
7- to 12-membered, preferably 9- or 10-membered unsaturated condensed heterocyclic group (preferably bicyclic group) having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl, or the like;
3- to 8-membered, preferably 5- or 6-membered unsaturated hetero monocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, 1,2-thiazolyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), or the like;
3- to 8-membered, preferably 5- or 6-membered saturated hetero monocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolydinyl;
3- to 8-membered, preferably 5- or 6-membered unsaturated hetero monocyclic group having one sulfur atom, such as thienyl or the like; etc.
Suitable xe2x80x9cesterified carboxyl groupsxe2x80x9d are exemplified below.
The ester portion of the esterified carboxyl group suitably include a lower alkyl ester, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, or hexyl ester, which may have at least one appropriate substituent. Examples of the lower alkyl ester include lower alkanoyloxy(lower)alkyl ester, such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxy methyl ester, 1-(or 2-)acetoxyethyl ester, 1-(2-, or 3-)acetoxypropyl ester, 1-(2-, 3- or 4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(2-, or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1(or 2-)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, or 1-(or 2-)pentanoyloxyethyl ester, lower alkanesulfonyl(lower)alkyl ester, such as 2-mesylethyl ester, mono(di, or tri)halo(lower)alkyl ester, such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester, lower alkoxycarbonyloxy(lower)alkyl ester, such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tertiary-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, or 1-(or 2-)isopropoxycarbonyloxyethyl ester, phthalizilidene(lower)alkyl ester or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester, such as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, or (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, lower alkenyl ester, such as vinyl ester or allyl ester, lower alkynyl ester, such as ethynyl ester or propinyl ester, ar(lower)alkyl ester which may have at least one appropriate substituent, such as benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, or 4-hydroxy-3,5-di-tertiary-butylbenzyl ester, aryl ester which may have at least one appropriate substituent, such as phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiary-butylphenyl ester, xylyl ester, mesityl ester, or cumenyl ester, phthalidyl ester, etc.
Preferable examples of a carboxyl groups protected by esterification include lower alkoxycarbonyl and phenyl(or nitrophenyl)(C1-C4)alkoxycarbonyl. Most preferred are methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl.
Suitable amidated carboxyl groups include the following:
a carbamoyl group;
a mono- or di-lower alkyl carbamoyl group (as a lower alkyl group, those as described above can be used), such as methylcarbamoyl, dimethylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, t-butylcarbamoyl, N-methyl-N-(pyridylmethyl)carbamoyl, or the like;
an aryl(lower alkyl)carbamoyl (as an aryl group and a lower alkyl group, those as described above can be used), such as benzylcarbamoyl, 3,4-methylenedioxybenzylcarbamoyl, diaminobenzylcarbamoyl, or phenethylcarbamoyl;
a cyclo(lower alkyl)carbamoyl having 3 to 7 carbon atoms (as a cyclo lower alkyl group, those as described above can be used), such as cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl or the like;
an arylcabamoyl group (as an aryl group, those as described above can be used), such as phenylcarbamoyl, naphthylcarbamoyl, or the like;
a heterocyclic carbamoyl group (as a heterocyclic group, those as described above can be used), such as thiazolylcarbamoyl, thiadiazolylcarbamoyl, pyridyl-carbamoyl, triazolylcarbamoyl, tetrazolylcarbamoyl, N-methyl-N-pyridinecarbamoyl, morpholinocarbamoyl, or the like;
a heterocyclic(lower alkyl)carbamoyl group (as a heterocyclic lower alkyl group, those as described above can be used), such as morpholinoethylcarbamoyl, pyridylmethylcarbamoyl, methylenedioxybenzylcarbamoyl, or the like;
an N-di-substituted carbamoyl group containing nitrogen as a member of a nitrogen-containing heterocyclic ring, such as morpholinocarbonyl, thiomorpholinocarbonyl, 1-perhydroazepinylcarbonyl, 1,1-dioxothiazolydinecarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, 4-(2-hydroxyethyl)-1-piperazinylcarbonyl, 4-methyl-1-piperazinylcarbonyl, carboxypyrrolidinocarbonyl, or the like;
a substituted sulfonylcarbomoyl group, etc.
The substituent for the substituted sulfonyl-carbamoyl group includes the above-described groups such as the alkyl group having carbon atoms up to 8, the halo lower alkyl group, the aryl lower alkyl group, the hydroxy-lower alkyl group, the tri(lower alkyl)silyl(lower alkyl) group, the lower alkoxy-lower alkyl group, the lower alkylthio-lower alkyl group, the heterocyclic group, the aryl group, and the like. The aryl group may be sutstituted by a halogen atom, a lower alkyl group a halo lower alkyl group, a lower alkoxy group, a nitro group, or the like. Specific examples of the substituted sulfonylcarbamoyl group include naphthylsulfonylcarbamoyl, benzenesulfonylcarbamoyl, nitrobenzenesulfonylcarbamoyl, trihalobenzenesulfonylcarbamoyal, lower alkoxybenzenesulfonylcarbamoyl, halobenzenesulfonylcarbamoyl, mono- or di-(lower alkyl)-benzenesulfonylcarbamoyl, alkanesulfonylcarbamoyl having 1 to 8 carbon atoms, such as t-butylsulfonylcarbamoyl, butylsulfonylcarbamoyl, propylsulfonylcarbamoyl, isopropylsulfonylcarbamoyl, methylsulfonylcarbamoyl, octylsulfonylcarbamoyl, pentylsulfonylcarbamoyl, isopentylsulfonylcarbamoyl, hexylsulfonylcarbamoyl, or the like, trihalo(lower)alkylsulfonylcarbamoyl, phenyl(lower)alkylsulfonylcarbamoyl, tri-(lower)alkylsulfonylcarbamoyl, lower alkylthio(lower) alkylsulfonylcarbamoyl, lower alkoxy(lower)alkylsulfonylcarbamoyl, quinolinesulfonylcarbamoyl, or the like.
Suitable acyl groups include aliphatic acyl, aromatic acyl, heterocyclic acyl, and aliphatic acyl substituted with an aromatic group or a heterocyclic group, which are derived from carboxylic acid, carbonic acid, sulfonic acid, carbamic acid, and the like.
Examples of the aliphatic acyl include saturated or unsaturated non-cyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkyl sulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxy carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, chlotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.) and the like.
Examples of the aromatic acyl include C6-C10 aroyl (e.g. benzoyl, toluoyl, xyloyl, etc.), N-(C6-C10)arylcarbamoyl (e.g. N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), C6-C10 arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like.
Examples of the heterocyclic acyl include heterocyclic carbonyl, heherocyclic(lower)alkanoyl (e.g. heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, heterocyclic pentanoyl, heterocyclic hexanoyl, etc.), heterocyclic(lower)alkenoyl (e.g. heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.) heterocyclic glyoxyloyl, heterocyclic sulfinyl, heterocyclic sulfonyl, etc.
The aromatic group-bound aliphatic acyl includes aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.).
These acyl groups may be substituted with one or more appropriate substituent, such as a nitro group. An example thereof is nitroaralkoxycarbonyl (e.g. nitrobenzyloxy-carbonyl, etc.).
Preferred salts of the benzimidazole derivatives of the present invention are non-toxic, ordinary pharmaceutically acceptable salts thereof. For example, mentioned are salts of the derivatives with bases as well as acid-addition salts of the derivatives, which include, for example, salts thereof with inorganic bases, such as salts with alkali metals (e.g., sodium, potassium); salts with alkaline earth metals (e.g., calcium, magnesium); ammonium salts; salts with organic amines (e.g., triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine); salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid); salts with organic carboxylic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid); salts with sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid); salts with basic or acidic amino acids (e.g., arginine, aspartic acid, glutamic acid), etc.
The compounds of the invention could contain one or more chiral centers, therefore they could be enantiomers or diastereomers. Few of the compounds containing alkenyl group could also be cis- or trans-isomers. In both cases, each of such isomers as well as the mixture thereof are within the scope of this invention.
The compounds of the invention can also exist as tautomers, and individual of such tautmers and the mixture thereof are within the scope of this invention.
The compounds of the invention and their salts can be solvate, which are also within the invention. The solvent for the solvate is preferably water or ethanol.
Specific examples of benzimidazole derivatives of formula (IX) include 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylbenzimidazole, 5-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, 5-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-5-(2-naphthalenesulfonylcarbamoyl)-benzimidazole, 1-(2-chlorobenzyl)-6-methanesulfonylcarbamoyl-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(1-octanesulfonylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(2-propanesufonylcarbamoyl)benzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole, 5-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole, N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acrylamide, N-benzenesulfonyl-2-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acetamide, 1-(2-chlorobenzyl)-2-methyl-6-(2-naphthalenesulfonylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(1-naphthalenesulfonylcarbamoyl)benzimidazole, 6-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole, 6-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-trifluoromethanesulfonylcarbamoylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(xcex1-toluenesulfonylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-6-(2,5-dimethylbenzenesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-[4-(trifluoromethyl)benzenesulfonylcarbamoyl]benzimidazole, 6-(2-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole, 5-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-hydroxybenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylaminobenzimidazole, 2-amino-6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-heptylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-chloromethylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxymethylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-i-propylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthiobenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylthiobenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylthiobenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-hexylthiobenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-methyl-1-(2-nitrobenzyl)benzimidazole, 6-benzenesulfonylcarbamoyl-2-methyl-1-benzylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazole, 6-benzenesulfonyl-carbamoyl-1-(4-benzyloxybenzyl)-2-methylbenzimidazole, 6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]propionamide, 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(8-quinolinesulfonylcarbamoyl)benzimidazole, 6-(4-t-butylbenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole, 5-benzenesulfonylcarbamoyl-2-methylbenzimidaozle, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole, 1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(1-propanesulfonylcarbamoyl)benzimidazole, 6-ethanesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-(propanesultam-1-ylcarbonyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-cyclopropylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-[(3-methylbutane)sulfonylcarbamoyl]benzimidazole, 1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-methylbenzimidazole, 7-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-[1-[3-(trimethylsilyl)propane]sulfonylcarbamoyl]benzimidazole, 4-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[(2xe2x80x2-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-(1-ethanesulfonyl-carbamoyl)-1-[(2xe2x80x2-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 1-(2-chlorobenzyl)-6-[(2-methoxyethane)-sulfonylcarbamoyl]-2-methylbenzimidazole, 1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(biphenyl-4-ylmethyl)-2-ethyl-6[1-[3-(methylthio)propane]sulfonylcarbamoyl]benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-ethylbenzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-[1-(3-methyl)butanesulfonylcarbamoyl]benzimidazole, 5-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(4biphenylmethyl)-5-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(2-methoxyethanesulfonylcarbamoyl)benzimidazole, 6-(1-butanesulfonylcarbamoyl)-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[sec-(2,4-dichlorophenethyl)]-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)benzyl]-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(4-phenoxybenzyl)benzimidazole, 6-(butanesufonylcarbamoyl)-2-methyl-1-(2-pyridylmethyl)benzimidazole, 1-[(4-benzoylamino)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethyl)benzyl]benzimidazole, 1-[(4-benzoyl)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethenyl)benzyl]-benzimidazole, 1-(dibenzofuran-2-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole, 6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(2-quinolylmethyl)benzimidazole, and 6-(1-butanesulfonylcarbamoyl)-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole, etc.
Specific examples of compounds of formula (X) include 1-(2-cyanobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 6-ethoxycarbonyl-2-N-propyl-1-(2-pyridylmethyl)benzimidazole, 6-ethoxycarbonyl-1-methyl-2-n-propylbenzimidazole, 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methylbenzimidazole, 6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methylbenzimidazole, 1-[2-(benzenesulfonylmethyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole, 1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole, 1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methyl-benzimidazole, 6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole, 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethylbenzimidazole, 6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole, 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole, 6-carboxy-1-methyl-2-n-propylbenzimidazole, 6-carboxy-2-n-propyl-1-i-propylbenzimidazole, 1-n-butyl-6-carboxy-2-n-propylbenzimidazole, 6-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole, 1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole, 6-carboxy-1-(2-methoxybenzyl)-2-methylbenzimidazole, 6-carboxy-1-(4-methoxybenzyl)-2-methylbenzimidazole, 6-carboxy-2-methyl-1-[2-(benzenesulfonylmethyl)benzyl]benzimidazole, 6-carboxy-1-(2-cyanobenzyl)-2-methylbenzimidazole, 6-carboxy-1-(biphenyl-2-ylmethyl)-2-methylbenzimidazole, 6-carboxy-2-methyl-1-(2-naphthylmethyl)benzimidazole, 1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole, 5-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole, 1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole, 1-(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole, 5-ethoxycarbonyl-2-methylbenzimidazole, 2-benzyl-5-ethoxycarbonylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole, 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole, 5-ethoxycarbonyl-2-trifluoromethylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-trifluoromethylbenzimidazole, 1-(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethylbenzimidazole, 1-methyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-n-propyl-1-i-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-n-butyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-benzyl-1-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-[2-(benzenesulfonylmethyl)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-cyanobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(biphenyl-2-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-naphthylmethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(biphenyl-4-ylmethyl)-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole, 2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-benzenesulfonyl-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-phenylethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-phenylethyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)aminomethyl]benzimidazole, 2-benzyl-6-carboxy-1-methylbenzimidazole, 4-ethoxycarbonyl-2-methylbenzimidazole, 1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 1-(4-benzyloxybenzyl)-6-carboxy-2-methylbenzimidazole, 6-ethoxycarbonyl-1-[(2xe2x80x2-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-carboxy-1-[(2xe2x80x2-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-ethoxycarbonyl-1-[(2xe2x80x2-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-carboxy-1-[(2xe2x80x2-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-carboxy-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 1-(4-biphenylmethyl)-5-ethoxycarbonyl-2-ethylbenzimidazole, 1-(4-biphenylmethyl)-5-carboxy-2-ethylbenzimidazole, 6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole, 6-carboxy-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole, 1-[4-(3,4-dichlorobenzyloxy)benzyl]-6-ethoxycarbonyl-2-ethylbenzimidazole, 6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole, 1-(4-biphenylmethyl)-6-(n-butylcarbamoyl)-2-ethylbenzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(thiazol-2-ylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(2-pyridylcarbamoyl)benzimidazole, 1-[sec-(2,4-dichlorophenethyl)]-6-ethoxycarbonyl-2-methylbenzimidazole, 6-carboxy-1-[sec-(2,4-dichlorophenethyl)]-2-methylbenzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(phenylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-thiadiazol-2-ylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(tetrazol-5-ylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-3-ylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-(1,3,4-triazol-2-ylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(3-pyridylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(4-pyridylcarbamoyl)benzimidazole, 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxycarbonylbenzimidazole, 6-carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-(4-phenoxybenzyl)benzimidazole, 6-carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole, 6-ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)benzimidazole, 6-carboxy-2-methyl-1-(2-pyridylmethyl)benzimidazole, 6-ethoxycarbonyl-2-methyl-1-(4-nitrobenzyl)benzimidazole, 1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole, 1-[(4-benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole, 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole, 6-carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole, 1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole, 1-[(4-benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole, 6-carboxy-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole, 1-(dibenzofuran-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 6-carboxy-1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)benzimidazole, 6-carboxy-2-methyl-(2-quinolylmethyl)-benzimidazole, 1-(2,4-dichlorobenzyl)-2-hydroxy-6-ethoxycarbonylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]-benzimidazole, and 6-carboxy-2-methyl-[3-(4-bromoisoquinolyl)methyl]benzimidazole, etc.
Specific examples of benzimidazole derivatives of formula (XI) include 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-phenylbenzimidazole, 2-benzyl-5-carboxy-1-(2-chlorobenzyl)benzimidazole, 2-benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole, 2-benzyl-5-carboxy-1-(2,4-dichlorobenzyl)benzimidazole, 2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole, 2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole, 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole, 2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole, 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole, 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid, methyl 1-(2-chlorobenzyl)-2-methyl-benzimidazole-6-acrylate, 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid, 1-(2-chlorobenzyl)-6-[2-(pyridylmethyl)carbamoyl]benzimidazole, 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethyl-benzimidazole, 1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole, 1-(4-benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethyl-benzimidazole, and 6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole, etc.
Specific examples of benzimidazole derivatives of formula (XII) include 6-t-butoxycarbonylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-6-mesylamino-2-n-propylbenzimidazole, 6-acetylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole, 6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-2-n-propyl-6-ureidobenzimidazole, 6-t-butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-amino-1-(2-chlorobenzyl)-2-methylbenzimidazole, and 6-(1-butanesulfonylamino)-1-(2-chlorobenzyl)-2-methylbenzimidazole, etc.
Specific examples of benzimidazole derivatives of formula (XIII) include 1-(2-chlorobenzyl)-6-cyano-2-cyclopropylbenzimidazole, and 1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole, etc. Specific examples of benzimidazole derivatives of formula (VI) include 1-(2-chlorobenzyl)-6-(4-dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-2-n-propyl-6-thiomorpholinocarbonylbenzimidazole, 1-(2-chlorobenzyl)-2-cyclopropyl-6-(2-pyridylcarbamoyl)benzimidazole, 6-(2-carboxy-1-pyrrolidinocarbonyl)-1-(2-chlorobenzyl)-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-6-piperonylcarbamoyl-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(homopiperidinocarbonyl)-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-6-[N-methyl-N-(2-pyridyl)carbamoyl]-2-n-propylbenzimidazole, 2-n-butyl-1-(2-(fluorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]benzimidazole, 2-cyclopropyl-1-(2-fluorobenzyl)-6-(piperonylcarbamoyl)benzimidazole, 2-[[1-(2-chlorobenzyl)-2-ethylbenzimidazol-6-yl]carbonylaminomethyl]pyridine-1-oxide, and 1-(2,4-dichlorobenzyl)-2-methyl-6-(2-pyridylcarbamoyl)benzimidazole, etc.
The present invention further includes, within its scope, the following novel benzimidazole derivatives: 1-(2-bromobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 6-ethoxycarbonyl-1-(2-fluorobenzyl)-2-n-propylbenzimidazole, 6-ethoxycarbonyl-1-(4-fluorobenzyl)-2-n-propylbenzimidazole, 6-ethoxycarbonyl-1-(3-fluorobenzyl)-2-n-propylbenzimidazole, 1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 1-(3-methylbenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 2-cyclopropyl-6-ethoxycarbonyl-1-(2-fluorobenzyl)-benzimidazole, 1-(2-chlorobenzyl)-2-cyclobutyl-6-ethoxycarbonylbenzimidazole, 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-n-pentylbenzimidazole, 5-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole, 6-carboxy-1-(3-methylbenzyl)-2-n-propylbenzimidazole, 2-n-butyl-7-carboxy-1-(2-chlorobenzyl)benzimidazole, 6-carboxy-1-(2-fluorobenzyl)-2-cyclopropylbenzimidazole, 2-n-butyl-6-carboxy-1-(2-fluorobenzyl)benzimidazole, 1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole, 1-(2-chlorobenzyl)-6-morpholinocarbamoyl-2-n-propylbenzimidazole, 2-n-butyl-1-(2-chlorobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-n-butyl-5-carbamoyl-1-(2-chlorobenzyl)benzimidazole, 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonylbenzimidazole, 1-(2-chlorobenzyl)-2-cyclopropyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-cyclobutyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-n-propyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-6-phenylcarbamoyl-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-2-n-propyl-6-[(4-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-n-propyl-6-[(3-pyridylmethyl)carbamoyl]benzimidazole, 1-(3-methylbenzyl)-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-n-butyl-1-(2-chlorobenzyl)-7-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-n-butyl-1-(2-fluorobenzyl)-6-(2-pyridylmethylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole, 1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole, 6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole, 1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)benzimidazole, 1-benzyl-6-ethoxycarbonyl-2-methylbenzimidazole, 1-(4-t-butylbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole, 1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, 6-carboxy-1-(4-chlorobenzyl)-2-n-propylbenzimidazole, 6-carboxy-1-(2,6-dichlorobenzyl)-2-methylbenzimidazole, 6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]benzinidazole, 6-carboxy-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole, 6-carboxy-1-(3,4-dichlorobenzyl)-2-methylbenzimidazole, 1-benzyl-6-carboxy-2-n-propylbenzimidazole, 6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole, 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(4-t-butylbenzyl)-6-carboxy-2-methylbenzimidazole, 6-carboxy-2-methyl-1-(2-methylbenzyl)benzimidazole, 1-benzyl-6-carboxy-2-methylbenzimidazole, 5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(3-chlorobenzyl)-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-benzyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-chlorobenzyl)-2-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2,6-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[2-(trifluoromethyl)benzyl]benzimidazole, 2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(trifluoromethyl)benzyl]benzimidazole, 1-(3,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-methylbenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-benzyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-t-butylbenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2,4-difluorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2,4-difluorobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2,4-dichlorobenzyl)-7-ethoxycarbonyl-2-methylbenzimidazole, 7-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole, 4-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole, 5-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, and 6-(n-butylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole.
The benzimidazole derivatives and their pharmaceutically acceptable salts of the present invention that are mentioned hereinabove are effective for preventing and treating various disorders of, for example, impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), and hypertension based on their blood sugar level-depressing activity, as well as stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerous cachexia, and restenosis after PTCA based on their cGMP-PDE (especially PDE-v)-inhibiting activity, smooth muscle relaxing activity, bronchodilating activity, vasodilating activity, smooth muscle cell suppressing activity, and antiallergic activity.
In addition, we, the present inventors, have further found that the benzimidazole derivatives which we have disclosed in Japanese Patent Application Laid-Open No. 5-222000 as c-GMP phosphodiesterase inhibitors also have the above-mentioned activities, and have now confirmed that these benzimidazole derivatives are also effective for preventing and treating the above-mentioned diseases and disorders like the compounds mentioned hereinabove.
Accordingly, the present invention further includes pharmaceutical compositions comprising, as an active ingredient, any of benzimidazole derivatives of the following formula (I) and their pharmaceutically acceptable salts, which are effective for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), or hypertension; or stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerous cachexia, or restenosis after PTCA. 
In formula (I):
R1 represents a hydrogen atom, an arylsulfonyl group, or a lower alkyl group; and said lower alkyl group may be substituted by an aryl group or an aryl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, an aryl-lower alkyl group, an aryl-lower alkyloxy group, a haloaryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, a cyanoaryl group, and a heterocyclic group, or by a heterocyclic group;
R2 represents a hydrogen atom, a lower cycloalkyl group, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, an amino group, a lower alkylamino group, a carboxyl group, an aryl group, or a lower alkyl group; and said lower alkyl group may be substituted by a halogen atom, a lower alkoxy group, a cyano group, a chlorocarbonyl group, an aryl group, or a heterocyclic group;
R3 represents a carboxyl group, an esterified carboxyl group, an amidated carboxyl group, an amino group, an amido group, or a sulfonyl group; and said amino group and said amido group may be substituted by an acyl group or a sulfonyl group; and a halogen atom, an amino group, or an acylamino group is bonded to said sulfonyl group; or R3 may be bonded to the skeleton via a lower alkylene or alkenylene group; and
R4 represents a neutral substituent. R4 includes a halogen atom, and a lower alkyl group, an aralkyl group, an alkynyl group, a lower alkyloxy group, and halogen-substituted groups of these. Where R4 is a hydrocarbon group, it may be either saturated or unsaturated, or either linear or cyclic, or may even be branched. For the halogen atom and the halogen-substituted groups, the kind of the halogen is not specifically defined. For the latter, the number of halogens substituted is not specifically defined.
n means an integer from 0 to 3. Thus, one, two or three R4s may be bonded to the skeleton, or no R4 may be bonded thereto. The position of R4 may be any of the ortho-position, the meta-position and the para-position relative to the other substituent.
Specific examples of benzimidazole derivatives of formula (I) include 2-butyl-1-(2-chlorobenzyl )-6-ethoxycarbonylbenzimidazole, 1-(4-bromo-2-fluorobenzyl)-2-butyl-6-ethoxycarbonylbenzimidazole, 2-butyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole, 2-butyl-6-ethoxycarbonyl-1-(4-methoxcarbonylbenzyl)benzimidazole, 2-butyl-6-ethoxycarbonyl-1-(2-fluorobenzyl)benzimidazole, 2-butyl-6-ethoxycarbonyl-1-(2-trifluoromethylbenzyl)benzimidazole, 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-ethylbenzimidazole, 1-(2-chlorobenzyl )-6-ethoxycarbonyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-2-cyclopropyl-6-ethoxycarbonylbenzimidazole, 1-(2-chlorobenzyl )-6-ethoxycarbonyl-2-isopropylbenzimidazole, 2-butyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole, 2-butyl-1-(2-chlorobenzyl)-7-ethoxycarbonylbenzimidazole, 1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-propylbenzimidazole, 2-butyl-1-(2-chlorobenzyl)-6-carboxybenzimidazole, 2-butyl-6-carboxy-1-(4-carboxybenzyl)benzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-ethylbenzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-propylbenzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-cyclopropylbenzimidazole, 2-butyl-5-carboxy-1-(2-chlorobenzyl)imidazole, 2-butyl-1-(2-chlorobenzyl)-6-dimethylcarbamoylbenzimidazole, 6-(benzylcarbamoyl)-2-butyl-1-(2-chlorobenzyl)benzimidazole, 2-butyl-1-(2-chlorobenzyl)-6-morpholinocarbonylbenzimidazole, 2-butyl-6-carbamoyl-(2-chlorobenzyl)-benzimidazole, 2-butyl-1-(2-chlorobenzyl)-6-(4-methylpiperazinyl)carbonylbenzimidazole, 2-butyl-1-(2-chlorobenzyl)-6-(methylcarbamoyl)benzimidazole, 6-carbamoyl-1-(2-chlorobenzyl)-2-ethylbenzimidazole, 6-carbamoyl-1-(2-chlorobenzyl)-2-propylbenzimidazole, 6-carbamoyl-1-(2-chlorobenzyl)-2-cyclopropylbenzimidazole, 2-butyl-5-carbamoyl-1-(2-chlorobenzyl)benzimidazole, 2-butyl-1-(2-chlorobenzyl)-6-(isopropylcarbonyl)benzimidazole, 1-(2-chlorobenzyl)-6-chloroformyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(methylcarbamoyl)-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(ethylcarbamoyl)-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(isopropyl)carbamoyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(piperidinocarbonyl)-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(morpholinocarbonyl)-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(2-morpholinoethyl)carbamoyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-[4-(2-hydroxyethyl)piperazinyl]carbonyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-2-propyl-6-(2-pyridylmethyl)carbamoylbenzimidazole, 1-(2-chlorobenzyl)-2-propyl-6-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]carbamoylbenzimidazole, etc.
To use the benzimidazole derivatives of the present invention for treating diseases or disorders such as those mentioned hereinabove, they may be formulated into pharmaceutical compositions of ordinary forms, which comprise, as an active ingredient, any of the derivatives along with pharmaceutically acceptable carriers, such as organic or inorganic solid or liquid vehicles, and which are suitable for peroral administration, parenteral administration or external application. The pharmaceutical compositions may be of any solid form of tablets, granules, powders, capsules, etc., or may be of any liquid form of solutions, suspensions, syrups, emulsions, lemonades, etc.
If desired, the pharmaceutical compositions may further contain a pharmaceutical aid, a stabilizer, a wetting agent, and also any ordinary additive of, for example, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, etc.
The amount of the above-mentioned derivative of the present invention to be used shall vary, depending on the age and the condition of patients, the type and the condition of diseases or disorders, and the type of the derivative to be used. In general, for peroral administration, the dose of the derivative may be from 1 to 100 mg/kg; and for intramuscular injection or intravenous injection, it may be from 0.1 to 10 mg/kg. Such a unit dose may be applied to a patient once to four times a day.